In 2019, PI3K inhibitors became a new treatment option for postmenopausal women and men with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer with the U.S. Food and Drug Administration’s approval of alpelisib in combination with fulvestrant. Although alpelisib remains the only PI3K inhibitor approved today, others are in clinical trials, and the new class of agents has a unique safety profile.